Universität zu Köln

Ng, Joanne ORCID: 0000-0002-7946-9965, Zhen, Juan ORCID: 0000-0002-6111-9692, Meyer, Esther, Erreger, Kevin, Li, Yan, Kakar, Naseebullah, Ahmad, Jamil, Thiele, Holger, Kubisch, Christian ORCID: 0000-0003-4220-0978, Rider, Nicholas L., Morton, D. Holmes, Strauss, Kevin A., Puffenberger, Erik G., D'Agnano, Daniela, Anikster, Yair, Carducci, Claudia, Hyland, Keith, Rotstein, Michael, Leuzzi, Vincenzo ORCID: 0000-0002-2314-6139, Borck, Guntram, Reith, Maarten E. A. and Kurian, Manju A. (2014). Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain, 137. S. 1107 - 1120. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Dopamine transporter deficiency syndrome is an SLC6A3-related progressive infantile-onset parkinsonism-dystonia that mimics cerebral palsy. Ng et al. describe clinical features and molecular findings in a new cohort of patients. They report infants with classical disease, as well as young adults manifesting as atypical juvenile-onset parkinsonism-dystonia, thereby expanding the disease spectrum.Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ng, Joanne UNSPECIFIED orcid.org/0000-0002-7946-9965 UNSPECIFIED Zhen, Juan UNSPECIFIED orcid.org/0000-0002-6111-9692 UNSPECIFIED Meyer, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Erreger, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kakar, Naseebullah UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahmad, Jamil UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED orcid.org/0000-0003-4220-0978 UNSPECIFIED Rider, Nicholas L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morton, D. Holmes UNSPECIFIED UNSPECIFIED UNSPECIFIED Strauss, Kevin A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Puffenberger, Erik G. UNSPECIFIED UNSPECIFIED UNSPECIFIED D'Agnano, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Anikster, Yair UNSPECIFIED UNSPECIFIED UNSPECIFIED Carducci, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Hyland, Keith UNSPECIFIED UNSPECIFIED UNSPECIFIED Rotstein, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Leuzzi, Vincenzo UNSPECIFIED orcid.org/0000-0002-2314-6139 UNSPECIFIED Borck, Guntram UNSPECIFIED UNSPECIFIED UNSPECIFIED Reith, Maarten E. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurian, Manju A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-442015
DOI:	10.1093/brain/awu022
Journal or Publication Title:	Brain
Volume:	137
Page Range:	S. 1107 - 1120
Date:	2014
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INFANTILE PARKINSONISM-DYSTONIA; NEUROTRANSMITTER TRANSPORTERS; HYPERACTIVITY DISORDER; MONOAMINE TRANSPORTERS; BACTERIAL HOMOLOG; BINDING-SITE; REVEALS; RELEASE; TRAFFICKING; MUTATIONS Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44201